(N-benzyl) acetaldehyde bicyclic heterocycles useful as topical antiinflammatories

ABSTRACT

(Indazol-1&#39;-ymethyl)phenylacetaldehydes as Topical Anti-inflammatories.

RELATED APPLICATION

This application is a division of U.S. application Ser. No. 07/860,775,filed Mar. 27, 1992, now U.S. Pat. No. 5,217,983.

BACKGROUND OF THE INVENTION

1. Field Of The Invention

This invention relates to novel (N-benzyl)acetaldehyde bicyclicheterocycles, pharmaceutical compositions containing them, and methodsof using them to treat skin inflammation, for example psoriasis, inmammals.

2. Background

Many diseases of the skin and muco-epithelia, such as psoriasis, arecharacterized by an inflammatory reaction in the underlying connectivetissue and a hyperplasia (increased mitotic activity) of the overlyingepithelia. Agents which suppress either or both the inflammatory andmitotic activity of the epithelia are effective in treating diseases ofthe skin.

The current treatment for skin and muco-epithelial diseases (i.e.psoriasis and chronic dermatitis) is primarily based upon topicalsteroids. These are efficacious but have significant side effects suchas skin atrophy, rosacea and adrenal suppression and thus are limited intheir chronic stage.

A second common treatment for psoriasis is the use of coal tar or itsderivatives. This treatment is unpleasant, not very effective and haspotential for carcinogenesis. For moderate to severe cases of psoriasis,psoralens with UVA or drugs such as methotrexate or cyclosporin A, whoseside effects are kidney failure or liver toxicity, have been used withsuccess.

A clear need exists for better treatment of skin diseases, particularlytreatments which can provide at the same time effective, safe andcosmetically acceptable results. The compounds of this invention offerpromise for providing such treatment.

SUMMARY OF THE INVENTION

This invention relates (N-benzyl)acetaldehyde bicyclic heterocyclesuseful as topical anti-inflammatories. More specifically, the inventionrelates to (indol-1'-ylmethyl)-, (indazol-1'-ylmethyl)-,(benzimidazol-1'-ylmethyl)-, and(benzotriazol-1'-ylmethyl)-phenylacetaldehydes, pharmaceuticalcompositions containing them, and methods of using them to topicallytreat skin inflammation in mammals. These compounds have the generalformula: ##STR1## wherein X and Y independently are CH or N;

R¹ is H, F, Cl, Br, C₁ -C₄ alkyl phenyl,

benzyl, or OR² where R² is C₁ 14 C₄ alkyl;

provided that

when R¹ is other than H, R¹ is other than at the 7-position;

when X and Y are N and R¹ is other than H, R¹ is at the 4-position;

when X is CH and Y is N, R¹ is other than F; and

when X and Y are N, R¹ is other than Br, F, phenyl or benzyl.

Preferred compounds of formula (I) are those in which the --CH₂ CHOgroup is present at the paraposition of the designated aromatic ring.Also preferred are those compounds of formula (I) in which X is CH and Yis N, X is N and Y is CH, or X and Y are both N.

Illustrative of the most preferred compounds of formula (I) are thefollowing:

4-(benzimidazol-1'-ylmethyl)phenylacetaldehyde

4-(indizol-1'-ylmethyl)phenylacetaldehyde

4-(benzotriazol1'-ylmethyl)phenylacetaldehyde

DETAILED DESCRIPTION

The compounds of formula (I) can be prepared according to the generalsynthetic route outlined in Scheme 1. Thus, compounds of formula (II)can be treated with an appropriate base, for example potassium hydride,followed by treatment with an appropriate alpha-bromotolunitrile. Theresulting compounds of formula (III) can then be reduced usingdiisobutylaluminum hydride (DIBAH) followed by treatment with diluteacid, for example acetic acid, to provide compounds of formula (IV).Treatment of (IV) with base-treated (methoxymethyl)triphenylphosphoniumchloride can provide compounds of formula (V). Treatment of compounds offormula (V) with mercuric acetate followed by dilute, aqueous potassiumiodide results in formation of compounds of formula (I).

The compounds of formula (II), if not commercially available, can beobtained by one skilled in the art. Thus, compounds of formula (II), inwhich X and Y are CH, can be prepared by following the procedures andmethods outlined in the "The Chemistry of Heterocyclic Compounds:Indoles," Vol. 25 (Part 1), Wiley-Interscience, New York, 1972.Similarly, the compounds of formula (II), in which X is nitrogen and Yis CH, can be prepared by methods described in "The Chemistry ofHeterocyclic Compounds: Pyrazoles, Pyrazolines, Pyrazolidines, Indazolesand Condensed Rings," Vol. 22, pp. 289-382, Interscience Publishers, NewYork, 1967. Also, the compounds of formula (II), in which X is CH and Yis nitrogen, can be prepared by procedures outlined in "The Chemistry ofHeterocyclic Compounds: Benzimidazoles and Congeneric TricyclicCompounds," Vol. 40 (Part 1), pp. 1-285, John Wiley and Sons;Interscience, New York, 1981. Finally, the compounds of formula (II), inwhich X and Y are nitrogen, can be prepared by one skilled in the artfrom the procedures described by Phillip H. Morgan and Karl F. Hussung,Trans. Ky. Acad. Sci. 39 (1-2), 23-30 (1978) for R₁ =4-Cl; Curt Wentrupand Wilfred D. Crow, Tetrahedron 26 (16), 3965 (1970) for R₁ =4-Me; andR. Lawrence and Eric S. Wright, Org. Mass Spectrum. 3 (3), 467-77 (1970)for R₁ =4-OMe. ##STR2##

EXAMPLES Example 1 Part A: 4-(benzimidazol-1'-ylmethyl)benzonitrile

A mixture of 11.45 g (100 mmol) of potassium hydride (35% dispersion inoil) and 150 mL dry tetrahydrofuran was stirred at room temperatureunder nitrogen. Added portionwise was 11.80 g (100 mmol) ofbenzimidazole and the mixture stirred 10 minutes. Added next was 25.0 g(125 mmol) alpha-bromo-p-tolunitrile, dropwise in 75 mL drytetrahydrofuran, and the mixture stirred at reflux for 2 hours. Thereaction was allowed to cool to room temperature and carefully quenchedwith 5 mL of absolute methanol. The mixture was poured into 150 mL ofwater and extracted with 3×200 mL ethyl acetate. The organic layers werecombined, dried (anhydrous magnesium sulfate), filtered and solvent wasremoved. The residue was purified by flash chromatography on silica gelusing a mixture of ethyl acetate--hexanes--acetic acid (80:18:2) aseluant. Obtained was 18.6 g (79.8 mmol, 79.8%) of4-(benzimidazol-1'-ylmethyl)benzonitrile, mp=90°-92° C. (Nujol): 2229cm⁻¹. High resolution mass spectrum: Calculated; 233.0953. Measured;233.0955.

Part B: 4-(benzimidazol-1'-ylmethyl)benzaldehyde

A mixture of 10.6 g (45.0 mmol) 4-(benzimidazol-1'-ylmethyl)benzonitrileand 200 mL toluene was stirred at -78° C. under nitrogen. Added dropwisewas 45 mL (67.5 mmol) of 1.5 M (in toluene) diisobutylaluminum hydrideand the mixture was stirred at -78° C. for 2 hours followed by stirringat room temperature overnight. Carefully added was 100 mL of 5% aceticacid and the solution was stirred for 5 minutes at room temperature. Themixture was carefully neutralized with saturated sodium bicarbonate andextracted with 3×200 mL ethyl acetate. The organic layers were combined,dried (anhydrous magnesium sulfate), filtered and solvent was removed.The residue was purified by flash chromatography on silica gel using amixture of ethyl acetate--hexanes--acetic acid (80:18:2) as eluant.Obtained was 6.5 g (27.5 mmol, 61.2%) of4-(benzimidazol-1'-ylmethyl)benzaldehyde as a liquid. NMR (CDCl₃ /TMS):∂5.4 (s, 2H), 7.1-7.8 (m, 8H), 8.0 (s, 1H). IR (Neat): 1694 cm⁻¹. Highresolution mass spectrum: Calculated; 236.0949. Measured; 236.0959.

Part C: Mixture of (E)- and(Z)-1-(benzimidazol-1'-ylmethyl)-4-(2''-methoxyethenyl)benzene

A mixture of 4.27 g (37.0 mmol) potassium hydride (35% dispersion inoil) and 150 mL dry tetrahydrofuran was stirred at room temperatureunder nitrogen. Added portionwise was 12.85 g (37.0 mmol) of(methoxymethyl)triphenylphosphonium chloride and the mixture stirred for10 minutes Added dropwise, in 25 mL dry tetrahydrofuran, was 4.0 g (17.0mmol) of 4-(benzimidazol-1'-ylmethyl)benzaldehyde and the mixturestirred at reflux for 3 hours followed by stirring at room temperatureovernight. The reaction was carefully quenched with 5 mL absolutemethanol and poured into 150 mL of water. The mixture was extracted with3×100 mL ethyl acetate and the organic layers were combined, dried(anhydrous magnesium sulfate), filtered and solvent was removed. Theresidue was purified by flash chromatography on silica gel using ethylacetate as eluant. Obtained was 4.02 g (15.23 mmcl, 89.6%) of a mixtureof (E)- and(Z)-1-(benzimidazol-1'-ylmethyl)-4-(2''-methoxyethenyl)benzene as aliquid. NMR (CDCl₃ /TMS): ∂3.65 (2s, 3H), 5.25 (2s, 2H), 5.1-7.0 (m,2H), 7.0-7.9 (m, 9H). IR (Nujol): 2923 cm⁻¹ ; High resolution massspectrum: Calculated; 264.1263.

Part D: 4-(benzimidazol-1'-ylmethyl)phenylacetaldehyde

A mixture of 3.5 g (13.28 mmol) of a mixture of (E)- and(Z)-1-(benzimidazol-1'-ylmethyl)-4-(2''-methoxyethenyl)benzene, 340 mLtetrahydrofuran and 34 mL water was heated at reflux under nitrogen topurge the system free of oxygen. The mixture was allowed to cool to roomtemperature and added at once was 12.66 g (39.71 mmol) mercuric acetateand the solution stirred for one hour. The mixture was poured into 1000mL of 7% potassium iodide solution and extracted with 3×400 mL benzene.The combined organic layers were then washed sequentially with 200 ml of7% potassium iodide solution, 200 mL water and 200 mL brine. The organiclayer was dried (anhydrous magnesium sulfate), filtered and solvent wasremoved. The residue was purified by flash chromatography on silica gelusing a mixture of hexanes-ethyl acetate-methanol (55:35:10) as eluant.Obtained was 750 mg (3.00 mmol, 22.6%) of4-(benzimidazol-1'-ylmethyl)phenylacetaldehyde as a liquid. NMR (CDCl₃/TMS): ∂3.7 (d, 2H), 5.4 (s, 2H), 7.25-7.9 (m, 8H), 7.95 (s, IH), 9.75(t, 1H). IR (Neat): 1720 cm⁻¹. High resolution mass spectrum:Calculated; 250.1106. Measured; 250.1124.

Example 2 Part A: 4-(indizol-1'-ylmethyl)benzonitrile

A mixture of 960 mg (8.40 mmol) of potassium hydride (35% dispersion inoil) and 20 mL dry tetrahydrofuran was stirred at room temperature undernitrogen. Added portionwise was 1.0 g (8.40 mmol) of indazole and themixture stirred 5 minutes. Added next was 2.15 g (11.00 mmol)alpha-bromo-p-tolunitrile, dropwise in 5 mL dry tetrahydrofuran, and themixture stirred at room temperature for 2 days. The reaction wascarefully quenched with 1 mL of absolute methanol, poured into 50 mLwater, and extracted with 3×50 mL ethyl acetate. The organic layers werecombined, dried (anhydrous magnesium sulfate), filtered and solvent wasremoved. The residue was purified by flash chromatography on silica gelusing a mixture of hexanes --ethyl acetate (2:1) as eluant. The lesspolar of the two major fractions was isolated to provide 1.04 g (4.46mmol, 53%) of 4-(indazol-1'-ylmethyl)benzonitrile, mp=72-73° C. NMR(CDCl₃ /TMS): ∂5.65 (s, 2H), 7.15-7.8 (m, 8H), 8.05 (s, IH). IR (Nujol):2230 cm⁻¹. High resolution mass spectrum: Calculated ; 233.0953.Measured; 233.0955. The more polar of the two major fractions was alsoisolated to provide 600 mg (2.58 mmol, 30.6%) of4-(indazol-2'-ylmethyl)benzonitrile as a liquid. NMR (CDCl₃ /TMS): ∂5.65(s, 2H), 7.05-7.75 (m, 8H), 7.95 (s, 1H). IR (Neat): 2230 cm⁻¹. Highresolution mass spectrum: Calculated; 233.0953. Measured; 233.0952. Thetwo positional isomers described above were differentiated based on NMRas Elguero, et. al. (Bull. Soc. Chim. Fr. 6, 2075 (1966)).

Part B: 4-(indazol-1'-ylmethyl)benzaldehyde

A mixture of 10.0 g (42.0 mmol) 4-(indazol-1'-ylmethyl)benzonitrile and250 mL toluene was stirred at -78° C. under nitrogen. Added dropwise was42 mL (60.0 mmol) of 1.5M (in toluene) diisobutylaluminum hydride andthe mixture was stirred at -78° C. for 2 hours followed by stirring atroom temperature overnight. Carefully added was 100 mL of 5% acetic acidand the solution stirred for 5 minutes at room temperature. The mixturewas carefully neutralized with saturated sodium bicarbonate andextracted with 3×200 mL ethyl acetate. The organic layers were combined,dried (anhydrous magnesium sulfate), filtered and solvent was removed.The residue was purified by flash chromatography on silica gel using amixture of hexanes--ethyl acetate (2:1) as eluant. Obtained was 7.6 g(32.2 mmol, 76.6%) of 4-(indazol-1'-ylmethyl)benzaldehyde as a liquid.NMR (CDCl₃ /TMS): ∂5.7 (s, 2H), 7.15-7.85 (m, 8 H), 8.1 (s, 1H), 9.95(s, 1H). IR (Neat): 1695 cm⁻¹. High resolution mass spectrum:Calculated; 236.0949.

Part C: Mixture of (E)- and(Z)-1-(indazol-1'-ylmethyl)-4-(2''-methoxyethenyl)benzene

A mixture of 8.09 g (70.0 mmol) potassium hydride (35% dispersion inoil) and 300 mL dry tetrahydrofuran was stirred at room temperatureunder nitrogen. Added portionwise was 24.37 g (70.0 mmol) of(methoxymethyl)triphenylphosphonium chloride and the mixture stirred for10 minutes. Added dropwise in 50 mL dry tetrahydrofuran was 7.6 g (31.0mmol) of 4-(indazol-1'-ylmethyl)benzaldehyde and the mixture was stirredat reflux for 3 hours followed by stirring at room temperature for 2days. The reaction was carefully quenched with 5 mL absolute methanoland poured into 300 mL of water. The mixture was extracted with 3×200 mLethyl acetate and the organic layers were combined, dried (anhydrousmagnesium sulfate), filtered and solvent was removed. The residue waspurified by flash chromatography on silica gel using a mixture ofhexanes --ethyl acetate (4:1) as eluant. Obtained was 3.90 g (14.77mmol, 47.6%) of a mixture of (E)- and(Z)-1-(indazol-1'-ylmethyl)-4-(2''-methoxyethenyl)benzene as a liquidNMR (CDCl₃ /TMS): ∂3.7 (2s, 3H), 5.55 (2s, 2 H), 5.15-6.15 (m, 2H),6.95-8.05 (m, 9H). IR (Neat): 2933 cm⁻¹. High resolution mass spectrum:Calculated; 264.1263. Measured; 264.1252.

Part D: 4-(indazol-1'-ylmethyl)phenylacetaldehyde

A mixture of 3.5 g (13.28 mmol) of a mixture of (E)- and(Z)-1-(indazol-1'-ylmethyl)-4-(2''-methoxyethenyl)benzene, 340 mLtetrahydrofuran and 35 mL water was heated at reflux under nitrogen topurge the system free of oxygen. The mixture was allowed to cool to roomtemperature and added at once was 12.66 g (39.71 mmol) mercuric acetateand the solution stirred for one hour. The mixture was poured into 1000mL of 7% potassium iodide solution and extracted with 3×400 mL benzene.The combined organic layers were then washed sequentially with 200 mL of7% potassium iodide solution, 200 mL water and 200 mL brine. The organiclayer was dried (anhydrous magnesium sulfate), filtered and solvent wasremoved. The residue was purified by flash chromatography on silica gelusing a mixture of hexanes--ethyl acetate (2:1) as eluant. Obtained was450 mg (1.8 mmol, 13.6%) of 4-(indazol-1'-ylmethyl)phenylacetaldehyde,mp=57°-58° C. NMR (CDCl₃ /TMS): ∂3.6 (d, 2H), 5.55 (s, 2H), 7.05-7.3 (m,7H), 7.7 (d, IH), 8.0 (s, 1H), 9.65 (t, 1H). IR (Nujol): 1721 cm⁻¹. Massspectrum: m/z=251 (M +H)⁺.

Example 3 Part A: 4-(benzotriazol-1'-ylmethyl)benzonitrile

A mixture of 9.5 g (83.0 mmol) of potassium hydride (35% dispersion inoil) and 200 mL dry tetrahydrofuran was stirred at room temperatureunder nitrogen. Added portionwise was 10.0 g (83.0 mmol) ofbenzotriazole and the mixture stirred 10 minutes. Added next was 18.1 g(92.0 mmol) alpha-bromo-p-tolunitrile, dropwise in 100 mL drytetrahydrofuran, and the mixture heated and stirred at reflux overnight.The mixture was allowed to cool to room temperature and carefullyquenched with 5 mL absolute methanol. The solution was poured into 300mL water and extracted with 3×200 mL ethyl acetate. The organic layerswere combined, dried (anhydrous magnesium sulfate), filtered and solventwas removed. The residue was purified by flash chromatography on silicagel using a mixture of hexanes --ethyl acetate (2:1) as eluant. Obtainedwas 10.2 g (43.6 mmol, 52.5%) of4-(benzotriazol-1'-ylmethyl)benzonitrile, mp=144°-147° C. NMR (CDCl₃/TMS): ∂5.9 (s, 2 H), 7.3-7.7 (m, 7H), 8.15 (d, IH). IR (Nujol): 2225cm⁻¹. High resolution mass spectrum: Calculated; 234.0905. Measured;234.0908.

Part B: 4-(benzotriazol-1'-ylmethyl)benzaldehyde

A mixture of 9.8 g (41.88 mmol) 4-(benzotriazol-1'-ylmethyl)benzonitrileand 250 mL toluene was stirred at -78° C. under nitrogen. Added dropwisewas 42 mL (60.0 mmol) of 1.5 M (in toluene) diisobutylaluminum hydrideand the mixture stirred at -78° C. for 2 hours followed by stirring atroom temperature overnight. Carefully added was 100 mL of 5% acetic acidand the solution stirred for 5 minutes at room temperature. The mixturewas carefully neutralized with saturated sodium bicarbonate andextracted with 3×200 mL ethyl acetate. The organic layers were combined,dried (anhydrous magnesium sulfate), filtered and solvent was removed.The residue was purified by flash chromatography on silica gel using amixture of hexanes--ethyl acetate (1:1) as eluant. Obtained was 7.0 g(29.54 mmol, 70.5%) of 4-(benzotriazol-1'-ylmethyl)benzaldehyde,mp=133°-135° C. NMR (CDCl₃ /TMS): ∂5.85 (s, 2H), 7.25-8.1 (m, 8H), 9.9(s, 1H). IR (Nujol): 1688 cm⁻¹. High resolution mass spectrum:Calculated; 237.0902. Measured; 237,0905.

Part C: Mixture of (E)- and(Z)-1-(benzotriazol-1'-ylmethyl)-'-(2''-methoxyethenyl)benzene

A mixture of 7.21 g (63.0 mmol) of potassium hydride (35% dispersion inoil) and 250 mL dry tetrahydrofuran was stirred at room temperatureunder nitrogen. Added portionwise was 21.59 g (63.0 mmol) of(methoxymethyl)triphenylphosphonium chloride and the mixture stirred atroom temperature for 10 minutes. Added next was 6.8 g (28.0 mmol) of4-(benzotriazol-1'-ylmethyl)benzaldehyde in 50 mL dry tetrahydrofuran.The mixture was heated at reflux for 3 hours, allowed to cool to roomtemperature and stirred overnight. The reaction was quenched with 5 mLabsolute methanol and was poured into 300 mL water. The mixture wasextracted with 3×200 mL ethyl acetate. The organic layers were combined,dried (anhydrous magnesium sulfate), filtered and solvent was removed.The residue was purified by flash chromatography on silica gel using amixture of hexanes-ethyl acetate (2:1) as eluant. Obtained was 3.20 g(12.1 mmol, 43.2%) of a mixture of (E)- and(Z)-1-(benzotriazol-1'-ylmethyl)-4-(2''-methoxyethenyl)benzene as aliquid. NMR (CDCl₃ /TMS): ∂ 3.7 (2s, 3H), 5.8 (2s, 2H), 5.2-7.0 (m, 2H),7.2-8.15 (m, 8H). IR (Neat): 2935 cm⁻¹. High resolution mass spectrum:Calculated; 265.1215. Measured; 265.1216.

Part D: 4-(benzotriazol-1'-ylmethyl)phenyl-acetaldehyde

A mixture of 284 mg (1.07 mmol) of a mixture of (E)- and(Z)-1-(benzotriazol-1'-ylmethyl)-4-(2''-methoxyethenyl)benzene, 27 mLtetrahydrofuran and 2 mL water was heated at reflux under nitrogen topurge the system free of oxygen. The mixture was allowed to cool to roomtemperature and added was 1.02 g (3.20 mmol) mercuric acetate and themixture stirred for 45 minutes. The mixture was poured into 100 mL of 7%potassium iodide solution and then extracted with 3×75 mL benzene. Thecombined organic layers were then washed sequentially with 100 mL of 7%potassium iodide solution, 100 mL water and 100 mL brine. The organiclayer was dried (anhydrous magnesium sulfate), filtered and solvent wasremoved. The residue was purified by flash chromatography on silica gelusing a mixture of hexanes--ethyl acetate (3:2) as eluant. Obtained was80 mg (0.319 mmol, 29.8%) of4-(benzotriazol-1'-ylmethyl)phenylacetaldehyde, mp=100° -102° C. NMR(CDCl₃ /TMS): ∂3.6 (d, 2H), 5.8 (s, 2H), 7.1-7.4 (m, 7H), 8.0 (d, IH),9.65 (t, 1H). IR (Nujol): 1714 cm⁻¹. High resolution mass spectrum:Calculated; 250.0980. Measured; 250.1000.

Using the procedures of Examples 1-3 and Scheme I and the referencesabove, the following compounds shown in Table I can be prepared.

                  TABLE I                                                         ______________________________________                                        Example R.sub.1   --CH.sub.2 CHO position                                                                      X     Y                                      ______________________________________                                         4      H         ortho          CH    CH                                      5      4-Me      ortho          CH    CH                                      6      5-F       ortho          CH    CH                                      7      6-Cl      ortho          CH    CH                                      8      4-Br      ortho          CH    CH                                      9      6-OMe     ortho          CH    CH                                     10      4-Ph      ortho          CH    CH                                     11      5-CH.sub.2 Ph                                                                           ortho          CH    CH                                     12      H         meta           CH    CH                                     13      5-Me      meta           CH    CH                                     14      6-F       meta           CH    CH                                     15      4-Cl      meta           CH    CH                                     16      5-Br      meta           CH    CH                                     17      4-OMe     meta           CH    CH                                     18      5-Ph      meta           CH    CH                                     19      6-Ch.sub.2 Ph                                                                           meta           CH    CH                                     20      H         para           CH    CH                                     21      6-Me      para           CH    CH                                     22      4-F       para           CH    CH                                     23      5-Cl      para           CH    CH                                     24      6-Br      para           CH    CH                                     25      5-OMe     para           CH    CH                                     26      6-Ph      para           CH    CH                                     27      4-Ch.sub.2 Ph                                                                           para           CH    CH                                     28      H         ortho          CH    N                                      29      4-CH.sub.2 Ph                                                                           ortho          CH    N                                      30      H         meta           CH    N                                      31      4-Me      meta           CH    N                                      32      4-Br      meta           CH    N                                      33      4-Ph      meta           CH    N                                      34      4-Cl      para           CH    N                                      35      4-OMe     para           CH    N                                      36      H         ortho          N     CH                                     37      4-Me      ortho          N     CH                                     38      5-F       ortho          N     CH                                     39      4-Br      ortho          N     CH                                     40      6-OMe     ortho          N     CH                                     41      4-Ph      ortho          N     CH                                     42      5-Ch.sub.2 Ph                                                                           ortho          N     CH                                     43      H         meta           N     CH                                     44      5-Me      meta           N     CH                                     45      6-F       meta           N     CH                                     46      4-Cl      meta           N     CH                                     47      5-Br      meta           N     CH                                     48      5-Ph      meta           N     CH                                     49      6-CH.sub.2 Ph                                                                           meta           N     CH                                     50      5-Me      para           N     CH                                     51      6-F       para           N     CH                                     52      4-Cl      para           N     CH                                     53      5-Br      para           N     CH                                     54      4-OMe     para           N     CH                                     55      5-Ph      para           N     CH                                     56      6-CH.sub.2 Ph                                                                           para           N     CH                                     57      H         ortho          N     N                                      58      H         meta           N     N                                      59      4-Me      meta           N     N                                      60      4-Cl      para           N     N                                      61      4-OMe     para           N     N                                      ______________________________________                                    

UTILITY

Anti-inflammatory activities of the investigational compounds werestudied in murine skin using the following protocol. Edema was inducedby tetradecanoyl phorbol acteate (TPA) (1 μg/ear) [Marks, F.,Furstenberger, G., Kownatzki, E., Prostaglandin E Mediated Stimulationof Mouse Epidermis in vivo by Divalent Cation Ionophore A23187 and byTumor Promotor TPA, Cancer Res. 1981, 41:696-702]. Male CF-1 (CharlesRiver) 18°20 grams were used. Investigational compounds (in acetone at100 ug/ear) were applied to one ear just prior to application of theinflammagen. Four hours after TPA application, edema was determined bycomparing the weights of 6 mm punch biopsies from control (solvent) andinflammagen-treated ears. Percent inhibitions were calculated usingstandard equations. Results are shown in Table II below.

                  TABLE II                                                        ______________________________________                                        Compound         % Inhibition                                                 ______________________________________                                        Example 1 (Part D)                                                                             63                                                           Example 2 (Part D)                                                                             98                                                           Example 3 (Part D)                                                                             46                                                           ______________________________________                                    

The test results in Table II above show that the compounds describedherein effectively suppress the mitotic activity associated with mouseskin hyperplasia induced by TPA, indicative of efficacy in treatinghuman skin and muco-epithelial diseases such as psoriasis (in all itsforms), lichen planas, chronic eczema, icthyosis, pityriasis and chronicuticaria.

Dosage and Formulations

The compounds of formula (I) can be administered to treat skin andmuco-epithelial diseases such as psoriasis (in all its forms), lichenplanas, chronic eczema, icthyosis, pityriasis and chronic uticaria.These compounds may be administered by any means that produces contactof the active agent with the site of the disease on the body of amammal. They can be administered by any suitable means available for usein conjunction with pharmaceuticals, either as individual therapeuticagents or in a combination with steroid drugs, particularly topicalsteroids such as Synalar (fluocinolone acetonide), Lidex (fluocinolone),Westcort (hydrocortisone valerate), Valisone (betamethasone valeate),and Diprasone (betamethasone dipropionate). They can be administeredalone, but are generally administered with a pharmaceutical carrieraccording to standard pharmaceutical practice.

The dosage administered will, of course, vary depending upon knownfactors such as the pharmacodynamic characteristics of the particularagent, and its mode of administration; age, health, and weight of therecipient; nature and extent of symptoms, kind of concurrent treatment,frequency of treatment, and the effect desired. Usually a daily dosageof active ingredient can be about 0.1 to 100 milligrams per kilogram ofbody weight. Ordinarily 0.5 to 50, and preferably 1 to 10 milligrams perkilogram per day given in divided doses 1 to 6 times a day or insustained release form is effective to obtain desired results.

Dosage forms (compositions) suitable for topical administration containfrom about 1 milligram to about 500 milligrams of active ingredient perunit. In these pharmaceutical compositions the active ingredient willordinarily be present in an amount of about 0.5-5% by weight based onthe total weight of the composition.

The active ingredient can be administered topically as an ointment,cream or lotion. Useful pharmaceutical dosage forms for the topicaladministration of the compound useful in this invention can beillustrated as follows:

Topical Formulations

An ointment for topical administration is prepared at 70° C. by addingthe active ingredient to a mixture of 48% by weight white petrolatum,10% liquid petrolatum, 8% glycerol monostearate, 3% isopropyl myristateand 20% lanolin. After thorough mixing, a warm solution of methyl andpropyl parabens in water containing sodium acetone bisulfite is addedsuch that the final concentrations of each paraben is 0.15%, of water is8% and of sodium acetone bisulfite is 0.5%. The mixture is stirred untilit has reached room temperature.

A cream for topical administration is prepared at 75° C. by adding theactive ingredient to a mixture of 1% sodium lauryl sulfate, 12%propylene glycol, 25% stearyl alcohol, 25% white petrolatum and 37%water. The mixture is stirred until it congeals.

A gel for topical administration is prepared at 70° C. by adding theactive ingredient to a mixture of 0.75% Carbopol 940 (polycarbopol),46.25% water, 3% emulsifier hydroxylated lanolin, 50% ethanol and,optionally, 1-2% diisopropanolamine. The mixture is stirred until itcools to room temperature.

What is claimed is:
 1. A compound of formula (I) which is ##STR3## wherein X is N;Y is CH; R¹ is H, F, Cl, Br, C₁ -C₄ alkyl, phenyl, benzyl or OR² where R² is C₁ -C₄ alkyl, provided that when R¹ is other than H, R¹ is other than at the 7-position.
 2. A compound of claim 1 having the formula: ##STR4## wherein X is N;Y is CH; R¹ is H, F, Cl, Br, C₁ -C₄ alkyl; phenyl benzyl, or OR² where R² is C₁ -C₄ alkyl; provided that when R¹ is other than H, R¹ is other than at the 7-position.
 3. A compound of claim 2 which is 4-indazol-1'-ylmethyl)phenylacetaldehyde.
 4. A topical pharmaceutical composition consisting essentially of a carrier suitable for topical formulation and an efficacious amount of a compound having the formula: ##STR5## wherein X is N;Y is CH; R¹ is H, F, Cl, Br, C₁ -C₄ alkyl, phenyl, provided that when R¹ is other than H, R¹ is other than at the 7-position.
 5. The topical composition of claim 4 wherein the compound has the formula: ##STR6## wherein X is NY is CH; R¹ is H, F, Cl, Br, C₁ -C₄ alkyl, phenyl, benzyl or OR² where R² is C₁ -C₄ alkyl; provided that when R¹ is other than H, R¹ is other than at the 7-position.
 6. The topical composition of claim 5 wherein the compound is 4-(indazol-1'-ymethyl) phenylacetaldehyde.
 7. A method of treating a skin or mucoepithelial disease in a mammal comprising topically administering to the site of the disease on said mammal an efficaceous amount of a compound of the formula: ##STR7## wherein: X is N;Y is CH; R¹ is H, H, F, Cl, Br, C1-C4 alkyl, phenyl, benzyl or OR² where R² is C₁ -C₄ alkyl; provided that when R¹ is other than H, R¹ is other than at the 7-position.
 8. A method of treating a skin or mucoepithelial disease in a mammal comprising topically administering to the site of the disease on said mammal an efficaceous amount of a compound of the formula: ##STR8## wherein: X is CH;Y is N; R¹ is H, F, Cl, Br, C₁ -C₄ alkyl, phenyl, benzyl or OR² where R² is C₁ -C₄ alkyl; provided that when R¹ is other than H, R¹ is other than at the 7-position.
 9. The method of claim 8 wherein the compound is 4-(indazol-1'-ymethyl)phenylacetaldehyde. 